Abstract The pulmonary vasculature is unique in that it is subjected to a remarkable change in hemodynamic forces immediately after birth. Increase in oxygen tension with the first breath results in decreased pulmonary vascular resistance, which in conjunction with closure of the ductus arteriosus and foramen ovale, leads to marked increase in the blood flow through the pulmonary blood vessels. While the majority of infants can respond to such a change in hemodynamic forces via vascular stabilization and maturation, those in whom complications occur can succumb to respiratory failure and death. Neonatal pulmonary hemorrhage (NPH) is such a complication occurring in about 1 in 1000 births. We hypothesize that failure of proper maturation of the pulmonary arteries, involving disruption of flow induced ERK5 activation, is a key mechanism of NPH. Currently NPH lacks any well-defined etiology and conventional therapy remains mainly supportive. We propose to test the hypothesis that excess production of the growth factor Angiopoietin 2 (ANGPT2) in the lung, which results from disrupted ERK5 signaling, is a key therapeutically targetable mechanism in infants with NPH. Using a combination of mouse genetic and pharmacologic models and in vitro studies, we propose to test the relevant role of the ERK5-ANGPT2 pathway in promoting stabilization of the pulmonary vasculature in the pivotal newborn period. Our ultimate goal will be to develop new therapeutic strategies for NPH, which may be applicable to other contexts of pulmonary vascular instability.